Project Summary/Abstract: HIV-1 transmission to a new individual elicits a strong selective bottleneck on the existing virus population, and typically only one or a few very special viral variants will establish each new infection. Only very recently have transmitted/founder (T/F) HIV-1 variants been appreciated for their unique properties. Importantly, a vast majority of HIV-1 research has been performed utilizing lab-adapted or late-stage HIV-1 variants, which do not recapitulate the cell-tropism, unique resistance to interferon and restriction factors, and antigenic properties of T/F HIV-1 variants. Critically, the current animal model for HIV-1 infection and vaccine research, the rhesus macaque, does not support replication or even cellular entry of T/F HIV-1. However, our lab has discovered the first monkey, the Spix?s owl monkey, in which some (but not all) individuals encode a CD4 receptor that is broadly permissive for major global subtypes of T/F HIV-1 variants. This is quite compelling because owl monkeys are known to have minimal restriction factors against HIV-1. Further, HIV-1 with a single point mutation can be made to replicate in owl monkey kidney cells, indicating that all necessary cellular cofactors in owl monkey are compatible with this virus. There are two restriction factors in owl monkey T cells that are known to significantly inhibit HIV-1 replication, tetherin and TRIM-Cyp. Interestingly, the TRIM-Cyp block can be bypassed with a single mutation in the HIV-1 genome. Further, we and others have identified alleles of both CD4 and tetherin circulating within owl monkey populations that both do and do not block HIV-1. Therefore, the primary owl monkey T cell culture and infection system that I have developed provides a unique opportunity to map critical determinants for successful control of T/F HIV-1 infection. The objectives of this proposal are to demonstrate the importance of host genotype on T/F HIV-1 infection. The specific aims of this research proposal are to: 1) Determine whether receptors encoded by circulating CD4 and CCR5 alleles in four owl monkey colonies act as functional receptors for globally relevant subtypes of T/F HIV-1 Env, 2) Understand the interaction between owl monkey tetherin alleles and T/F HIV-1, and 3) Develop an owl monkey-tropic version of HIV-1 for investigating the T/F HIV-1 biology in primary cells and eventually in animals. I present preliminary data demonstrating that these studies will expand our understanding of T/F HIV-1 biology.